Thyroid hormone exerts marked influences on the contractile and electrophysiological function of the heart. Preliminary studies indicate that mice with a thyroid hormone receptor alpha1 (TRalpha1) knockout have bradycardia, decreased speed of papillary muscle relaxation and decreased levels of the RNA encoding the transient outward potassium current KV4.2. In contrast, TR beta 1 knockout mice have normal heart rate and normal KV4.2 levels but decreased RNA for the delayed rectifier channel KV1.5. The first aim will involve generating mice with a TRalpha knockout only in cardiac myocytes using the cre-lox system. Effects of the knockout on electrophysiological and contractile function will be determined. Gene expression of specific ion channel genes and other genes will also be determined. Cardiac effects of a novel T3 analog GC-1 will be explored. This analog has markedly decreased binding to TRalpha1 and a minimal effect on heart rate compared to T3. In aim 2 similar contractile, electrophysiological and gene expression studies will be performed on TR beta knockout mice. In addition mice with a knockout of both TR's will be generated and studied. In aim 3, the investigator will determine the mechanism of the specific TR isoform effects. Also the mechanisms of the effects of GC-1 will be studied.